This invention relates to semi-synthetic cyclic peptide compounds which are useful as antifungal agents and which have improved stability and water solubility. In particular, it relates to derivatives of the echinocandin class of cyclic peptides; to methods for treating fungal infections, and to formulations useful in the methods.
The compounds provided by this invention are semi-synthetic compounds derived from cyclic peptides which are produced by culturing various microorganisms. A number of cyclic peptides are known in the art including echinocandin B (A30912A), aculeacin, mulundocandin, sporiofungin and S31794/F1.
In general, these cyclic peptides may be structurally characterized as a cyclic hexapeptide core (or nucleus) with an acylated amino group on one of the core amino acids. The amino group is typically acylated with a fatty acid group forming a side chain off the nucleus. For example, echinocandin B has a linoleoyl side chain while aculeacin has a palmitoyl side chain.
The fatty acid side chains may be removed from the cyclic peptide core to provide an amino nucleus (for example, a compound of formula I, below, where R.sup.2 is hydrogen). The amino group may then be re-acylated to provide semi-synthetic compounds such as those claimed in the present application.
The echinocandin B nucleus has been re-acylated with certain non-naturally occurring side chain moieties to provide a number of antifungal agents (see, Debono, U.S. Pat. No. 4,293,489). Among such antifungal agents is cilofungin which is represented by a compound of formula I where R.sup.z1 and R.sup.z2 are each --CHOHCH.sub.3, R.sup.z3 is methyl; R.sup.x1 is hydrogen, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, R.sup.y4 and R.sup.0 is hydroxy and R.sub.2 is p-(octyloxy)benzoyl.